Deep vein thrombosis

Symptoms classically affect a leg and typically develop over hours or days, though they can develop suddenly or over a matter of weeks. The legs are primarily affected, with 4–10% of DVT occurring in the arms. In those who are able to walk, DVT can reduce one's ability to do so. The pain can be described as throbbing and can worsen with weight-bearing, prompting one to bear more weight with the unaffected leg. Additional signs and symptoms include tenderness, pitting edema (see image), dilation of surface veins, warmth, discoloration, a "pulling sensation", and even cyanosis (a blue or purplish discoloration) with fever. Rarely, a clot in the inferior vena cava can cause both legs to swell. Superficial vein thrombosis, also known as superficial thrombophlebitis, is the formation of a blood clot (thrombus) in a vein close to the skin. It can co-occur with DVT and can be felt as a "palpable cord". Potential complications A pulmonary embolism (PE) occurs when a blood clot from a deep vein (a DVT) detaches from a vein (embolizes), travels through the right side of the heart, and becomes lodged as an embolus in a pulmonary artery that supplies deoxygenated blood to the lungs for oxygenation. and can vary based upon where the embolus is lodged in the lungs. An estimated 30–50% of those with PE have detectable DVT by compression ultrasound. It is life-threatening, limb-threatening, and carries a risk of venous gangrene. Phlegmasia cerulea dolens can occur in the arm but more commonly affects the leg. If found in the setting of acute compartment syndrome, an urgent fasciotomy is warranted to protect the limb. Superior vena cava syndrome is a rare complication of arm DVT. File:SaddlePE.PNG|alt=A computed tomography image depicting PE in the pulmonary arteries|A CT image with red arrows indicating PE (grey) in the pulmonary arteries (white) File:PCD2016.jpg|alt=Image showing marked discoloration of a leg with phlegmasia cerulea dolens|A case of phlegmasia cerulea dolens in the left leg Patent-foramen-ovale-en.png|alt=A drawing depicting a patent foramen ovale|A depiction of a patent foramen ovale Differential diagnosis In most suspected cases, DVT is ruled out after evaluation. Cellulitis is a frequent mimic of DVT, with its triad of pain, swelling, and redness. superficial vein thrombosis, muscle vein thrombosis, and varicose veins. ==Classification==

DVT and PE are the two manifestations of the cardiovascular disease venous thromboembolism (VTE). DVT is classified as acute when the clots are developing or have recently developed, whereas chronic DVT persists for more than 28 days. An episode of VTE after an initial one is classified as recurrent. Bilateral DVT refers to clots in both limbs while unilateral means only a single limb is affected. DVT in a leg above the knee is termed proximal DVT (proximal). DVT in a leg below the knee is termed distal DVT (distal), also called calf DVT when affecting the calf, and has limited clinical significance compared to proximal DVT. Calf DVT makes up about half of DVTs. Iliofemoral DVT is described as involving either the iliac, or common femoral vein; elsewhere, it has been defined as involving at a minimum the common iliac vein, which is near the top of the pelvis. DVT can be classified as provoked and unprovoked. The distinction between these categories is not always clear. ==Causes==

Traditionally, the three factors of Virchow's triad—venous stasis, hypercoagulability, and changes in the endothelial blood vessel lining—contribute to VTE and were used to explain its formation. More recently, inflammation has been identified as playing a clear causal role. Other related causes include activation of immune system components, the state of microparticles in the blood, the concentration of oxygen, and possible platelet activation. Previous VTE, particularly unprovoked VTE, is a strong risk factor. Major surgery and trauma increase risk because of tissue factor from outside the vascular system entering the blood. hip fracture, and long bone fractures are also risks. paralysis, sitting, long-haul travel, bed rest, hospitalization, catatonia, and in survivors of acute stroke. Conditions that involve compromised blood flow in the veins are May–Thurner syndrome, where a vein of the pelvis is compressed, and venous thoracic outlet syndrome, which includes Paget–Schroetter syndrome, where compression occurs near the base of the neck. Infections, including sepsis, COVID-19, HIV, and active tuberculosis, increase risk. Chronic inflammatory diseases and some autoimmune diseases, such as inflammatory bowel disease, systemic sclerosis, Behçet's syndrome, primary antiphospholipid syndrome, increase risk. SLE itself is frequently associated with secondary antiphospholipid syndrome. Cancer can grow in and around veins, causing venous stasis. It can also stimulate higher levels of tissue factor. Cancers of the blood, lung, pancreas, brain, stomach, and bowel are associated with high VTE risk. Solid tumors such as adenocarcinomas can contribute to both VTE and disseminated intravascular coagulation. In severe cases, this can lead to simultaneous clotting and bleeding. Chemotherapy treatment also increases risk. Obesity increases the potential of blood to clot, as does pregnancy. In the postpartum, placental tearing releases substances that favor clotting. Oral contraceptives and hormonal replacement therapy increase the risk through various mechanisms, including altered blood coagulation protein levels and reduced fibrinolysis. system, often described as a "cascade", includes a group of proteins that regulate clotting. Abnormalities in the cascade can alter the risk of DVT. The regulators, antithrombin (ᾳTHR) and activated protein C (APC), are shown in green above the clotting factors they affect.|alt=Imagine showing the coagulation, which includes a group of proteins that regulate clotting. Abnormalities in the cascade can alter the risk of DVT. Dozens of genetic risk factors have been identified, mildly increases VTE risk by about three times. Having a non-O blood type roughly doubles VTE risk. Individuals without O blood type have higher blood levels of von Willebrand factor and factor VIII than those with O blood type, increasing the likelihood of clotting. The genetic variant prothrombin G20210A, which increases prothrombin levels, hyperhomocysteinemia, paroxysmal nocturnal hemoglobinuria, nephrotic syndrome, chronic kidney disease, polycythemia vera, essential thrombocythemia, intravenous drug use, and smoking. Some risk factors influence the location of DVT within the body. In isolated distal DVT, the profile of risk factors appears distinct from proximal DVT. Transient factors, such as surgery and immobilization, appear to dominate, whereas thrombophilias and age do not seem to increase risk. Common risk factors for having an upper extremity DVT include having an existing foreign body (such as a central venous catheter, a pacemaker, or a triple-lumen PICC line), cancer, and recent surgery. ==Pathophysiology==

Blood has a natural tendency to clot when blood vessels are damaged (hemostasis) to minimize blood loss. Clotting is activated by the coagulation cascade, and the clearing of clots that are no longer needed is accomplished by the process of fibrinolysis. Reductions in fibrinolysis or increases in coagulation can increase the risk of DVT. DVT most frequently affects veins in the leg or pelvis including the popliteal vein (behind the knee), femoral vein (of the thigh), and iliac veins of the pelvis. Extensive lower-extremity DVT can even reach into the inferior vena cava (in the abdomen). Upper extremity DVT most commonly affects the subclavian, axillary, and jugular veins. This is the preferred process. Aside from the potentially deadly embolization process, a clot can resolve through organization, which can damage venous valves, cause venous fibrosis, and result in non-compliant veins. and brachiocephalic veins (not pictured). The cephalic and basilic veins, however, are superficial. but clotting in the veins mostly occurs without any such mechanical damage. NETs provide "a scaffold for adhesion" of platelets, red blood cells, and multiple factors that potentiate platelet activation. In addition to the pro-coagulant activities of neutrophils, multiple stimuli cause monocytes to release tissue factor. Monocytes are also recruited early in the process. Hospitalized patients often have elevated levels for multiple reasons. ==Diagnosis== A clinical probability assessment using the Wells score (see column in the table below) to determine if a potential DVT is "likely" or "unlikely" is typically the first step of the diagnostic process. The score is used in suspected first lower extremity DVT (without any PE symptoms) in primary care and outpatient settings, including the emergency department. it does have drawbacks. The Wells score requires a subjective assessment regarding the likelihood of an alternate diagnosis and performs less well in the elderly and those with a prior DVT. The Dutch Primary Care Rule has also been validated for use. It contains only objective criteria but requires obtaining a D-dimer value. With this prediction rule, three points or less means a person is at low risk for DVT. A result of four or more points indicates an ultrasound is needed. Three compression ultrasound scanning techniques can be used, with two of the three methods requiring a second ultrasound some days later to rule out the diagnosis. Whole-leg ultrasound is the option that does not require a repeat ultrasound, Ultrasound methods including duplex and color flow Doppler can be used to characterize the clot further File:Iliac vein deep vein thrombosis.JPEG|An abdominal CT scan demonstrating an iliofemoral DVT, with the clot in the right common iliac vein of the pelvis File:Vascular anatomy lower extremity for DVT POCUS.png|Vascular anatomy for deep venous thrombosis (DVT) point of care ultrasound (POCUS) ==Management==

Treatment for DVT is warranted when the clots are either proximal, distal, and symptomatic, or upper extremity and symptomatic. Providing anticoagulation, or blood-thinning medicine, is the typical treatment after patients are checked to make sure they are not subject to bleeding. Although, those with isolated distal DVT at a high risk of VTE recurrence are typically anticoagulated as if they had proximal DVT. Those at low risk of recurrence might receive a four- to six-week course of anticoagulation, lower doses, or no anticoagulation at all. The benefit of taking warfarin declines as the duration of treatment extends, and the risk of bleeding increases with age. Periodic INR monitoring is not necessary when first-line direct oral anticoagulants are used. Overall, anticoagulation therapy is complex, and many circumstances can affect how these therapies are managed. The duration of anticoagulation therapy (whether it will last 4 to 6 weeks, When proximal DVT is provoked by surgery or trauma a 3-month course of anticoagulation is standard. Those who finish warfarin treatment after idiopathic VTE with an elevated D-dimer level show an increased risk of recurrent VTE (about 9% vs about 4% for normal results), and this result might be used in clinical decision making. Thrombophilia test results rarely play a role in the length of treatment. Treatment for acute leg DVT is suggested to continue at home for uncomplicated DVT instead of hospitalization. Factors that favor hospitalization include severe symptoms or additional medical issues. Early walking is suggested over bedrest. Graduated compression stockings—which apply higher pressure at the ankles and a lower pressure around the knees as the potential benefit of using them for this goal "may be uncertain". They are, however, recommended in those with isolated distal DVT. It is only about 33% as effective as anticoagulation in preventing recurrent VTE. Investigations for cancer An unprovoked VTE might signal the presence of an unknown cancer, as it is an underlying condition in up to 10% of unprovoked cases. It is not recommended practice to obtain tumor markers or a CT of the abdomen and pelvis in asymptomatic individuals. have not established a net benefit in those with acute proximal DVT. Drawbacks of catheter-directed thrombolysis (the preferred method of administering the clot-busting enzyme Catheter-directed thrombolysis with thrombectomy Phlegmasia cerulea dolens might be treated with catheter-directed thrombolysis and/or thrombectomy. File:Gray966.png|The first rib, which is removed in a first rib resection surgery, is labeled 1 in this image File:A-case-of-Paget-Schroetter-syndrome-(PSS)-in-a-young-judo-tutor-a-case-report-13256 2016 848 Fig1 HTML.jpg|A venogram before catheter-directed thrombolysis for Paget–Schroetter syndrome, a rare and severe arm DVT shown here in a judo practitioner, with highly restricted blood flow shown in the vein File:A-case-of-Paget-Schroetter-syndrome-(PSS)-in-a-young-judo-tutor-a-case-report-13256 2016 848 Fig2 HTML.jpg|After treatment with catheter-directed thrombolysis, blood flow in the axillary and subclavian vein was significantly improved. Afterwards, a first rib resection allowed decompression. This reduces the risk of recurrent DVT and other sequelae from thoracic outlet compression. Other studies including a systematic review and meta-analysis did not find a difference in mortality with IVC placement. If someone develops a PE despite being anticoagulated, care should be given to optimize anticoagulation treatment and address other related concerns before considering IVC filter placement. Patients suspected of having an acute DVT are often referred to the emergency department for evaluation. Interventional radiology is the specialty that typically places and retrieves IVC filters, and vascular surgery might do catheter directed thrombosis for some severe DVTs. ==Prevention==

For the prevention of blood clots in the general population, incorporating leg exercises while sitting down for long periods, or having breaks from a sitting position and walking around, having an active lifestyle, and maintaining a healthy body weight are recommended. Walking increases blood flow through the leg veins. Excess body weight is modifiable, unlike most risk factors, and interventions or lifestyle modifications that help someone who is overweight or obese lose weight reduce DVT risk. Statins have been investigated for primary prevention (prevention of a first VTE), and the JUPITER trial, which used rosuvastatin, has provided some tentative evidence of effectiveness. Of the statins, rosuvastatin appears to be the only one with the potential to reduce VTE risk. If so, it appears to reduce risk by about 15%. Hospital (non-surgical) patients Acutely ill hospitalized patients are suggested to receive a parenteral anticoagulant, although the potential net benefit is uncertain. recommend anticoagulation for the acutely ill in cases of elevated risk when neither bleeding nor a high risk of bleeding exists. Mechanical prophylaxis is suggested when risks for bleeding and thrombosis are elevated. For the critically ill, either pharmacological or mechanical prophylaxis is suggested depending upon the risk. Heparin can also be used in outpatients with cancer who have solid tumors and additional risk factors for VTE—listed as "previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide"—and a low risk of bleeding.--> After surgery , a procedure that can precipitate DVT formation Major orthopedic surgery—total hip replacement, total knee replacement, or hip fracture surgery—has a high risk of causing VTE. If prophylaxis is not used after these surgeries, symptomatic VTE has about a 4% chance of developing within 35 days. Following major orthopedic surgery, a blood thinner or aspirin is typically paired with intermittent pneumatic compression, which is the preferred mechanical prophylaxis over graduated compression stockings. After low-risk surgeries, early and frequent walking is the best preventive measure. Pregnancy The risk of VTE is increased in pregnancy by about four to five times because of a more hypercoagulable state that protects against fatal postpartum hemorrhage. Preventive measures for pregnancy-related VTE were suggested by the American Society of Hematology in 2018. Travelers Travelling "is an often cited yet relatively uncommon" cause of VTE. Graduated compression stockings have sharply reduced the levels of asymptomatic DVT in airline passengers, but the effect on symptomatic DVT, PE, or mortality is unknown, as none of the individuals studied developed these outcomes. However, graduated compression stockings are not suggested for long-haul travelers (>4 hours) without risk factors for VTE. Likewise, neither aspirin nor anticoagulants are suggested in the general population undertaking long-haul travel. ==Prognosis==

DVT is most frequently a disease of older age that occurs in the context of nursing homes, hospitals, and active cancer. If proximal DVT is left untreated, in the following 3 months approximately half of people will experience symptomatic PE. Post-thrombotic syndrome can also be a complication of distal DVT, though to a lesser extent than with proximal DVT. In the 10 years following an initial VTE, about 30% of people will have a recurrence. Cancer and unprovoked DVT are strong risk factors for recurrence. In upper extremity DVT, annual VTE recurrence is about 2–4%. After surgery, a provoked proximal DVT or PE has an annual recurrence rate of only 0.7%. ==Epidemiology==

About 1.5 out of 1000 adults a year have a first VTE in high-income countries. Children in North America and the Netherlands have VTE rates that range from 0.07 to 0.49 out of 10,000 children annually. though there are ages when VTE is more prevalent in women. VTE occurs in association with hospitalization or nursing home residence about 60% of the time, active cancer about 20% of the time, and a central venous catheter or transvenous pacemaker about 9% of the time. During pregnancy and after childbirth, acute VTE occurs in about 1.2 of 1000 deliveries. Despite it being relatively rare, it is a leading cause of maternal morbidity and mortality. After surgery with preventive treatment, VTE develops in about 10 of 1000 people after total or partial knee replacement, and in about 5 of 1000 after total or partial hip replacement. About 400,000 Americans develop an initial VTE each year, with 100,000 deaths or more attributable to PE. Asian, Asian-American, Native American, and Hispanic individuals have a lower VTE risk than white or Black people. Non-O blood type is present in around 50% of the general population and varies with ethnicity, and it is present in about 70% of those with VTE. DVT occurs in the upper extremities in about 4–10% of cases, ==Social==

has spoken at length about a frightening encounter she had with VTE while she was hospitalized in 2017. Head injuries prompting brain bleeds are of particular concern. This has caused NASCAR driver Brian Vickers to forgo participation in races. Professional basketball players including NBA players Victor Wembanyama, Chris Bosh, and hall of famer Hakeem Olajuwon have dealt with recurrent blood clots, and Bosh's career was significantly hampered by DVT and PE. Tennis star Serena Williams was hospitalized in 2011 for PE thought to have originated from DVT. Years later, in 2017, due to her knowledge of DVT and PE, Serena accurately advocated for herself to have a PE diagnosed and treated. During this encounter with VTE, she was hospitalized after a C-section surgery and was off blood thinners. After feeling the sudden onset of a PE symptom, shortness of breath, she told her nurse and requested a CT scan and an IV heparin drip, all while gasping for air. She started to receive an ultrasound to look for DVT in the legs, prompting her to express dissatisfaction with the medical staff, who were not looking for clots where she had symptoms (her lungs), and they were not yet treating her presumed PE. After being diagnosed with PE and not DVT, and after receiving heparin IV, the coughing from the PE caused her C-section surgical site to open, and the heparin contributed to bleeding at the site. Serena later received an IVC filter while in the hospital. Other notable people have been affected by DVT. Former United States President Richard Nixon had recurrent DVT, and so has former Secretary of State Hillary Clinton. She was first diagnosed while First Lady in 1998 and again in 2009. Dick Cheney was diagnosed with an episode while Vice President, and TV show host Regis Philbin had DVT after hip-replacement surgery. DVT has also contributed to the deaths of famous people. For example, DVT and PE played a role in rapper Heavy D's death at age 44. NBC journalist David Bloom died at age 39 while covering the Iraq War from a PE that was thought to have progressed from a missed DVT, and actor Jimmy Stewart had DVT that progressed to a PE when he was 89. History The book Sushruta Samhita, an Ayurvedic text published around 600–900 BC, contains what has been cited as the first description of DVT. In 1271, DVT symptoms in the leg of a 20-year-old male were described in a French manuscript, which has been cited as the first case or the first Western reference to DVT. In 1856, German physician and pathologist Rudolf Virchow published his analysis after the insertion of foreign bodies into the jugular veins of dogs, which migrated to the pulmonary arteries. These foreign bodies caused pulmonary emboli, and Virchow was focused on explaining their consequences. He cited three factors, which are now understood as hypercoagulability, stasis, and endothelial injury. It was not until 1950 that this framework was cited as Virchow's triad, Diagnoses were commonly performed by impedance plethysmography in the 1970s and 1980s, but ultrasound, particularly after the utility of probe compression was demonstrated in 1986, became the preferred diagnostic method. Multiple pharmacological therapies for DVT were introduced in the 20th century: oral anticoagulants in the 1940s, subcutaneous injections of LDUH in 1962 and subcutaneous injections of LMWH in 1982. 1974 was when vascular inflammation and venous thrombosis were first proposed to be interrelated. For around 50 years, a months-long warfarin (Coumadin) regimen was the mainstay of pharmacological treatment. To avoid the blood monitoring required with warfarin and the injections required by heparin and heparin-like medicines, direct oral anticoagulants (DOACs) were developed. The New York Times described a "furious battle" among the three makers of these drugs "for the prescription pads of doctors". Economics VTE costs the US healthcare system about $7 to 10 billion annually. In Europe, the costs for an initial VTE hospitalization are significantly less, costing about €2000 to 4000 (2011 estimate). Post-thrombotic syndrome is a significant contributor to DVT follow-up costs. Outpatient treatment significantly reduces costs, and treatment costs for PE exceed those of DVT. ==Research directions==

A 2019 study published in Nature Genetics reported more than doubling the known genetic loci associated with VTE. In their updated 2018 clinical practice guidelines, the American Society of Hematology identified 29 separate research priorities, most of which related to patients who are acutely or critically ill. ==Notes==